The effect of the nephrotoxic metals, cadmium, uranium, lead, copper and mercury, on the immature kidney is being evaluated by administering each metal to rats and rabbits at various ages beginning in the newborn period, and analyzing the functional effects and the changes in the enzyme distribution and content and the morphology of the nephron using tubules isolated by microdissection after collagenase treatment. The effects of each metal on the immature and mature nephron are used to determine whether the developing nephron is more susceptible than the mature nephron and to correlate such susceptibility with alterations in enzyme activity and morphology of the proximal tubule. The expected higher susceptibility of the immature nephron may allow detection of an effect of heavy metals which would be missed in the mature animal. The location of enzymes along the proximal tubule is determined by histochemical staining reactions of dissected nephrons. This makes it possible to detect both changes in the site or relative concentration of enzymes in various portions of the proximal tubule. The qualitative histochemical changes are corroborated by quantitative biochemical analysis of both dissected nephrons and homogenates of renal cortex. Electron microscopy is used to detect structural alterations of the proximal tubular cell produced by each toxin, and the combination of the morphologic and enzymatic alterations is used to adduce the mechanisms by which heavy metals inhibit the function of the proximal tubule. Both acute and chronic toxicity studies are being carried out to determine whether adaptive changes occur in chronic poisoning and to simulate the effect on the kidney of chronic environmental exposure to these toxins which might be expected to have permanent effects in the kidney. BIBLIOGRAPHIC REFERENCES: Weinberg, A.G. Mize, C.E. and Worthen, H.G.: The occurrence of hepatoma in the chronic form of hereditary tyrosinemia. J. Pediat. 88: 434, 1976. Worthen, H.G. and Mize, C.E.: Treatment of Metabolic Disorders, in Pediatric Therapy, Shirkey, H.C., Eichenwald, H.F., Worthen, H.G.F., et al (Eds.), C.V. Mosby, St. Louis, 1975, Chapter 109, p. 800.